Clinical characteristics and outcomes of B-cell precursor ALL with MEF2D rearrangements: a retrospective study by the Ponte di Legno Childhood ALL Working Group
Authors: Kentaro Ohki, Ellie R. Butler, Nobutaka Kiyokawa, Shinsuke Hirabayashi, Anke K. Bergmann, Anja Möricke, Judith M. Boer, Hélène Cavé, Giovanni Cazzaniga, Allen Eng Juh Yeoh, Masashi Sanada, Toshihiko Imamura, Hiroto Inaba, Charles G. Mullighan, Mignon L. Loh, Ulrika Norén-Nyström, Lee-Yung Shih, Marketa Zaliova, Ching-Hon Pui, Oskar A. Haas, Christine J. Harrison, Anthony V. Moorman, Atsushi Manabe
Journal: Leukemia (2022)

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) comprises multiple genetic subtypes with strong prognostic associations.The outcome of patients with high-risk genetics improves with risk stratification or targeted therapy [1,2].Therefore, it is important to assess the prognostic impact of newly identified genetic abnormalities to ensure appropriate clinical intervention.Recent studies have identified MEF2D rearrangements (MEF2D-r) in 2-3% cases and initial observations, based on small numbers of cases, indicate that patients have a poor outcome [3][4][5][6][7].MEF2D-r are characterized by fusion of an N-terminal region of MEF2D to the C-terminal region of multiple, different partner genes [3][4][5][6][7][8].As there are limited data available concerning the prognostic impact of MEF2D-r in ALL, we conducted an international study via the Ponto di Legno Childhood Leukemia Working Group to describe the clinical characteristics and outcome of patients with BCP-ALL and MEF2D-r.Demographic, clinical, treatment, genetics and outcome data were collected from 14 regional study groups (Supplementary Table 1).Patients were diagnosed between 1987 and 2018 and MEF2D-r were detected retrospectively, using a range of techniques (Supplementary Table 2).The majority of cases [97/ 107(91%)] were identified by screening diagnostic samples from representative cohorts of B-other-ALL (i.e.patients lacking an established genetic abnormality).Additional cases were identified among relapse patients and/or in relapse samples.These cases were excluded from the survival analysis (n = 10).We considered three endpoints: relapse rate (RR), event-free survival (EFS) and overall survival (OS), using the Kaplan-Meier method, log-rank test and Cox regression models, retrospectively, as previously described [9].All rates are quoted at 5 years.Among 107 MEF2D-r patients, there was female predominance (66:41) with a median age of 10.67 years (Table 1).A quarter of patients had diagnostic peripheral blood white blood cell (WBC) counts >50,000/μl, which, coupled with the older age, resulted in 70% (60/98) being classified as National Cancer Institute (NCI) high risk.Data on antigen expression were available for 91 of the 107 cases.Different panels were used so the amount of data was variable for each antigen (Supplementary Table 3).Cases distributed evenly across EGIL groups: pro-B, pre-B, late pre-B.HLA-DR, cytoplasmic immunoglobulin μ chain, CD45, CD22 and CD19 were commonly expressed (>80% tested cases).CD10 and CD5 were expressed in 65% and 56% tested cases, respectively.None of the other tested antigens (CD2, CD3, CD7, CD13, CD20, CD33, CD34 and CD66c) were expressed in >20% tested cases.Unfortunately, data were unavailable for CD38 expression, which has reported to be a feature of .Although we did not include a comparator cohort, we confirmed the distinct features associated with MEF2D-r reported in smaller studies [3][4][5][6][7][8].Namely female sex, older age, common expression of cytoplasmic